Physiological modulators of Kv3.1 channels adjust firing patterns of auditory brainstem neurons

Author(s): Maile Reed Brown 1), Lynda El-Hassar 1), Yalan Zhang 1), Giuseppe Alvaro 2), Charles H Large 2), and Leonard K. Kaczmarek 3)

Many rapidly firing neurons, including those in the Medial Nucleus of the Trapezoid Body (MNTB) in the auditory brainstem, express “high threshold” voltage-gated Kv3.1 potassium channels that activate only at positive potentials and are required for stimuli to generate rapid trains of actions potentials. We now describe the actions of two imidazolidinedione derivatives, AUT1 and AUT2, which modulate Kv3.1 channels. Using CHO cells stably expressing rat Kv3.1 channels, we found that lower concentrations of these compounds shift the voltage of activation of Kv3.1 currents towards negative potentials, increasing currents evoked by depolarization from typical neuronal resting potentials. Single channel recordings also showed that AUT1 shifted the open probability of Kv3.1 to more negative potentials. Higher concentrations of AUT2 also shifted inactivation to negative potentials. The effects of lower and higher concentrations could be mimicked in numerical simulations by increasing rates of activation and inactivation respectively, with no change in intrinsic voltage-dependence. In brain slice recordings of mouse MNTB neurons, both AUT1 and AUT2 modulated firing rate at high rates of stimulation, a result predicted by numerical simulations. Our results suggest that pharmaceutical modulation of Kv3.1 currents represents a novel avenue for manipulation of neuronal excitability, and has the potential for therapeutic benefit in the treatment of hearing disorders.